Sarcopenia, the loss of muscle mass and function due to muscle fiber loss and atrophy, is a prominent and debilitating age-related consequence in humans. There is a need for a healthy aging model system to efficiently evaluate potential interventions that delay or reduce sarcopenia of the aged. We defined the onset of significant muscle mass and fiber loss in the Fischer 344 x Brown Norway hybrid rat (FBN) at 30 months of age. Our studies have demonstrated that mitochondrial DNA (mtDNA) abnormalities play a causal role in muscle fiber loss. We have shown that age-dependent mtDNA deletion mutations clonally accumulate to high levels in aged skeletal muscle fibers. Concomitant with this increase in aberrant genomes is a loss of complex IV (cytochrome c oxidase; COX-) activity of the electron transport system (ETS) and the hyper-reactivity of complex II (succinate dehydrogenase; SDH++). These COX-/SDH++ regions of abnormal fibers are prone to atrophy and breakage, linking a molecular event, mtDNA deletion mutations, with an aging phenotype, muscle fiber loss. Endurance training is a common intervention employed by the elderly to combat the loss of muscle mass and function that occurs with age. Very little, however, is known of the impact of this intervention in very old humans or animals. We have recently completed a study showing that 3 months of high intensity endurance training, initiated at 30 months of age in the male FBN rat, increased the prevalence of ETS abnormal fibers, a detrimental process that leads to fiber loss. Our data is consistent with a rapidly growing body of literature that indicates the level of exercise necessary for beneficial adaptation declines with age. We hypothesize that the benefits/risks of aerobic exercise is dependent on i) the age at which aerobic exercise is initiated and ii) the intensity level of the exercise. To test this hypothesis, we will initiate two levels of exercise (moderate and high) prior to (24-month-old rats; SA1) and at the onset (30-month-old rats; SA2) of significant accumulation of mitochondrial abnormalities, muscle mass loss and fiber loss in male FBN rats. The sarcopenic profiles (muscle morphology and fiber fate) will be determined in control rats (sedentary at 24-. 30 and 36 months) and experimental rats at 36-months of age. These analyses will define muscle mass, muscle cross-sectional area, fiber number, fiber cross-sectional area, fiber type and fibrotic infiltration, as well as the number of fibers exhibiting necrotic and apoptotic changes. The impact of exercise on the abundance and progression and mtDNA deletion load will be determined in affected fibers (SA 3). We will also ascertain if single fibers with high mtDNA deletion loads have altered contractile function and whether exercise alters the mechanical properties of affected single fibers (SA4). This exercise model will serve as a means of testing our proposed mechanism of age-related fiber loss as well as further our understanding of the impact of aerobic exercise in aged skeletal muscle. An important outcome of these studies is to determine if endurance training, a commonly employed intervention of sarcopenia, can be beneficial to muscle health in old mammals. 1